Reactivation of latent toxoplasmosis leads to encephalitis (TE) and is one of the most common life threatening central nervous system infections in HIV infected patients. Although incidence as a result of cART therapy has decreased substantially, it continues to be a problem in countries with high prevalence of infection. It is believed that reactivation of latent toxoplasmosis occurs during advanced stages of HIV infection, when CD8 T cell response is compromised. In mouse model of encephalitis, we have reported severe dysfunctionality in memory CD8+ T cell population due to graded up- regulation of PD-1 (a well-known inhibitory molecule) expression on these cells. Although PD-1-PDL-1 blockade invigorated CD8+ T cell response, highly exhausted memory CD8+ T cells could not be rescued. Preliminary data for the proposal demonstrates that in addition to PD-1, CD8+ T cells from susceptible animals exhibited increased expression of other inhibitory molecules like LAG-3, 2B4 and CTLA-4. Thus blockade of multiple inhibitors may be needed to restore the functionality of memory CD8+ T cells. Further, to develop effective therapies against this chronic infection, mechanism responsible for CD8 dysfunction needs to be defined. The proposal has three specific aims. In aim 1, kinetics and pattern of multiple inhibitory receptors expressed by memory CD8+ T cells from infected animals will be performed. This will provide important information about the antibody cocktail needed for reversing the dysfunctionality in this population. In aim 2, the mechanism of memory CD8+ T cell dysfunction during chronic toxoplasma infection will be evaluated. Based on our preliminary findings, in this specific aim the mechanism involved in the IL-21 mediated maintenance of CD8+T functionality will be deciphered. Finally in the third aim, underlying causes responsible for decreased IL-21 response in animals susceptible to TE with reference to CD40 signaling will be performed. Information generated from these studies will be highly beneficial to develop therapeutic regimen that will enable to maintain robust CD8+T cell memory against chronic toxoplasma infection, which continues to be a serious problem for HIV, infected population.